A Possible Link Between HCN Channels and Depression

Abstract

Growing evidence suggests a possible link between hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels and depression. In a recent study published in Molecular Psychiatry, we first demonstrate that I _h (the membrane current mediated by HCN channels) and HCN1 protein expression were increased in dorsal, but not in ventral, CA1 region following chronic, but not acute stress. This upregulation of I _h was restricted to the perisomatic region of CA1 neurons and contributed to a reduction of neuronal excitability. A reduction of HCN1 protein expression in dorsal CA1 region before the onset of chronic unpredictable stress-induced depression was sufficient to provide resilient effects to chronic unpredictable stress. Furthermore, in vivo block of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, a manipulation known to increase intracellular calcium levels and upregulate I _h, produced anxiogenic-like behavior and an increase in I _h, similar to that observed in chronic unpredictable stress model of depression. Here, we share our view on (1) how the function and expression of HCN1 channels are changed in the brain in a subcellular region-specific manner during the development of depression and (2) how a reduction of HCN1 protein expression provides resilience to chronic stress.

Keywords: HCN1; Ih; chronic unpredictable stress; hippocampus; resilience.

Figure 1.

Perisomatic upregulation of functional I_h regulate depressive behaviors following CUS. (A) Representative illustration of development of depression following CUS and recovery. (B) Depressive-like symptoms gradually increased with increasing duration of CUS. These depressive-like symptoms decreased following four-week recovery period. (C) Neuronal excitability is gradually decreased with increasing duration of CUS. This CUS-induced a decrease in neuronal excitability do not occur after a four-week recovery period. (D) Perisomatic increases in I_h-sensitive electrophysiological measurement (i.e., resonance frequency, fR) and HCN1 protein expression along the somatodendritic region of dorsal CA1. AP: action potential; CUS: chronic unpredictable stress; HCN: hyperpolarization-activated cyclic nucleotide-gated nonselective cation; SLM: stratum lacunosum moleculare; SR: stratum radiatum; SO: stratum oriens; SP: stratum pyramidale.

Figure 2.

A reduction of functional I_h in dorsal CA1 region/neurons confers resiliency to CUS. (a) Representative illustration of development of resilience to CUS. (b and c) Changes in functional I_h and neuronal excitability of lentiviral-shRNA-infected dorsal CA1 neurons (i.e., shRNA-control and shRNA-HCN1) before and after development of depression. (D and E) A reduction of HCN1 protein expression leads to increases in fEPSPs, hippocampal activity, mature BDNF, and pmTOR protein expression. AP: action potential; BDNF: brain-derived neurotrophic factor; CUS: chronic unpredictable stress; fEPSP: field excitatory postsynaptic potential; HCN: hyperpolarization-activated cyclic nucleotide-gated nonselective cation; pmTOR phosphorylation of mTOR.